CaMKII is a multifunctional protein kinase known for its critical role in learning and memory. CaMKII is highly expressed in the brain, but at least one of its four isoforms (α, β, γ and δ) has been found in every cell type examined to date. Numerous cellular functions of CaMKII have been described, both in and outside the nervous system. Some of these functions include regulation of various ion channels, gene expression, cell cycle/proliferation control, apoptotic and excitotoxic cell death cell morphology and filopodia motility. CaMKII is also implicated in regulation of insulin secretion, although studies suggesting this were largely based on KN inhibitors that also affect Ca2+-channels required for secretion.
CaMKII forms multimeric holoenzymes and a CaM-dependent inter-subunit auto-phosphorylation at T286 renders the kinase active even after dissociation of Ca2+/CaM. T286 is located in the regulatory region; its phosphorylation relieves auto-inhibition by preventing binding of the region around T286 to the T-site, which is adjacent to the substrate binding S-site. The Ca2+-independent or autonomous activity has been regarded as a form of “molecular memory”, and is important in several neuronal functions of the kinase. Additionally, T286 phosphorylation traps CaM on CaMKII, and regulates CaMKII binding to other proteins, such as syntaxin, densin-180, NR1, NR2A, NR2B, and F-actin. Among the other auto-phosphorylation sites, functions of T305/306 are understood best. T305/306 auto-phosphorylation can occur in an intra-subunit reaction, blocks CaM binding, accelerates CaMKII dissociation from synaptic sites, and also plays a role in learning.